Methylphenidate (Ritalin,.TM. Ciba-Geigy Corporation, Summit, N.J.) is the most commonly prescribed psychotropic medication for children in the United States. It is used primarily for the treatment of children diagnosed with attention deficit disorder (ADD). Methylphenidate is synonymous with methyl .alpha.-phenyl-2-piperidineacetate, .alpha.-phenyl-2-piperidineacetate methyl ester, methyl phenidylacetate, and methylphenidan. The biologically active form of methylphenidate is the D-threo enantiomer. Methylphenidate is sold, in the form of the hydrochloride salt, as the product Ritalin.TM. and its generic equivalents. A comprehensive description of the compound is found in Padmanabhan (1981, Analytical Profiles of Drug Substances v. 10, Florey, Ed., Academic Press, New York).
D-threo-methylphenidate is a mild central nervous system stimulant. Its mode of action in humans is not fully understood, but presumably involves activation of the brain stem arousal system to effect stimulation of the patient. Dosing and administration information, contraindications, warnings, and precautions pertaining to administration of methylphenidate to humans is available in the art (e.g. Physician's Desk Reference.RTM., Medical Economics Co., Inc., Montvale, N.J., 51st ed., 1997; PDR.RTM. Generics.TM., Medical Economics Co., Inc., Montvale, N.J., 2nd ed., 1996). Methylphenidate is the treatment of choice for attention deficit disorder, and is also used in the treatment of narcolepsy, minimal cerebral dysfunction, and other conditions. In addition, methylphenidate and its analogs have been proposed as cocaine antagonists for treatment of cocaine abuse and addiction (e.g. International Patent Application PCT/US99/00711 and Deutsch et al., 1996, J. Med. Chem. 39:1201-1209).
Numerous methods for synthesizing methylphenidate, for interconverting the diastereomers of methylphenidate, and for resolving the enantiomers of methylphenidate have been described in the art (U.S. Pat. No. 2,507,631 to Hartmann; U.S. Pat. No. 2,838,519 to Rometsch; U.S. Pat. No. 2,957,880 to Rometsch; British Patent Nos. 788,226 and 878,167, each to Ciba Ltd.; Soviet Patent No. 466,229 to Yakhontov et al.; International Patent Application Publication No. WO9735836 of Fox et al.; International Patent Application Publication No. WO9728124 of Langston et al.; Panizzon, 1944, Helv. Chim. Acta 27:1748-1756; Naito et al., 1964, Chem. Pharm. Bull. 12:588-590; Deutsch et al., 1996, J. Med. Chem. 39:1201-1209; Earle et al., 1969, J. Chem. Soc. (C) 2093-2098); International Patent Application Publication No. WO9825902 of Faulconbridge et al.; Patrick et al., 1987, J. Pharmacol. Exp. Therapeut. 241:152-158 International Patent Application Publication No. WO9727176 of Harris et al.; International Patent Application Publication No. WO9825902 of Zavareh. These methods have various shortcomings, including low yield, the necessity to interconvert diastereomers of methylphenidate following synthesis, and the necessity to resolve enantiomers of methylphenidate. Furthermore, investigation of methylphenidate analogs has been hampered by the fact that these methods can be used to synthesize only a narrow range of analogs, such as methylphenidate analogs having ester modifications or phenyl ring substitutions.
The present invention overcomes the shortcomings of these synthetic methods, and provides D-threo-methylphenidate and numerous D-threo-methylphenidate derivatives, including efficacious cocaine antagonists and analogs useful for treatment of various neurological disorders.